Obesity and related metabolic disorders, as a result of over-nutrition and reduced physical activity, are common health issues in modern societies. Exercise, notably endurance training has been shown to increase metabolic fitness and improve symptoms of the metabolic syndrome. Endurance exercise is an energy-demanding process, which triggers a systemic metabolic response to provide energy supply to support exercise physiology. This includes a transition from glycolytic to oxidative metabolism in prolonged exercise. This metabolic reprogramming is met with specialized muscle fibers exhibiting distinct energy substrate preferences and performances. Although exercise-associated metabolic benefits have been well documented in humans and animal models, the underlying mechanisms remain unclear. Several factors have been suggested to mediate certain exercise-induced metabolic effects within muscle and between muscle and other metabolically active tissues. IL-6 is one of the ?myokines? whose production is rapidly increased after exercise but its level at the resting state declines with endurance training. We have found that the Th2 cytokine IL-13 and type 2 innate lymphoid (ILC2) cells that produce IL-13 are induced in muscle of mice trained on a treadmill. Circulating IL-13 levels are also increased in humans with endurance exercise training. Preliminary data indicate IL-13 acts directly on muscle cells to control mitochondrial respiration. The current proposal will test the hypothesis that IL-13 signaling regulates muscle metabolic adaptation in endurance exercise by promoting mitochondrial oxidative metabolism through a novel IL-13-IL-13R?1-STAT3 regulatory mechanism. We believe the potential scientific impact and human health relevance of the current study is high, as results derived from the research plan will help our understanding of mechanisms mediating metabolic benefits of endurance exercise.